SymFold: Synergizing Evolutionary and Structural Priors for Accurate Protein Inverse Folding

Protein language models (pLMs) produce per-residue representations that capture evolutionary and structural information, yet their mean-pooled sequence embeddings are not explicitly trained to reflect functional, evolutionary or structural similarity between proteins. We present Protein Sentence Transformers (ProtSent), a contrastive fine-tuning framework for adapting PLMs into general-purpose embedding models. ProtSent trains with MultipleNegativesRankingLoss across five protein-pair datasets: Pfam families, structurally derived hard negatives, AlphaFold DB structural pairs, and StringDB protein--protein interactions, and Deep Mutational Scanning data. We evaluate on 23~downstream tasks using frozen embeddings with a k-nearest-neighbor probe to measure embedding neighborhood quality. On ESM-2 150M, ProtSent improves 15 of 23 tasks, with gains of +105% on remote homology detection, +17% on variant effect prediction, and +19.9% Recall@1 on SCOPe-40 structural retrieval. The 35M variant improves 16 of 23 tasks with +40.5% on remote homology and +15.5% Recall@1 on SCOPe-40. Contrastive fine-tuning restructures the embedding space to better capture protein function and structure, without any task-specific supervision. We release the models, public data, and training recipe and code.

How do protein structure prediction models fold proteins? We investigate this question through causal interventions on the folding trunks of ESMFold, OpenFold, and Boltz-1. Across all three models, we find a shared two-stage computational structure. In the first stage, early blocks initialize pairwise biochemical signals: features like charge propagate from sequence into pairwise representations through architecture-specific pathways. In the second stage, late blocks develop pairwise spatial features: distance and contact information accumulate in the pairwise representation. We verify these mechanisms causally by showing that steering charge and distance features induces predictable structural changes. Furthermore, these representations are functionally interchangeable: pairwise states can be linearly aligned and substituted across models. Together, these results suggest that folding trunks with different architectures, inputs, and training procedures converge on a shared representational organization for mapping sequence chemistry into spatial geometry.

Protein structure generative models excel at predicting single protein static structures from sequence, but routinely fail to capture the correct conformational state of protein complexes, critical for protein design and induced proximity modalities such as antibodies and PROTACs. While structural proteomics techniques like Cross-Linking Mass Spectrometry (XL-MS) and Hydrogen-Deuterium Exchange (HDX-MS) offer valuable spatial and dynamic insights, integrating these sparse, heterogeneous measurements into these models remains an open challenge. Here, we bridge this gap by combining structural proteomics data with the rich biophysical priors learned by pretrained diffusion models. We introduce AIMS-Fold, an inference-time guided-diffusion framework that actively steers the generative sampling trajectory using differentiable physical potentials derived from XL-MS spatial restraints and HDX-MS solvent accessibility profiles. We demonstrate that these structural methods individually enhance predictive accuracy, and their integration yields synergistic improvement. Crucially, by leveraging these experimental restraints, AIMS-Fold achieves higher accuracy on challenging induced proximity targets than purely computational, unguided state-of-the-art models like Boltz-2. This establishes our framework as a powerful, integrative computational approach for the structure based drug design of induced proximity drugs. Evaluation code will be made publicly available upon publication.